Synergistic association of the copper/zinc ratio under inflammatory conditions with diabetic kidney disease in patients with type 2 diabetes: The Asahi Diabetes Complications Study.

AIMS/INTRODUCTION: We aimed to study the relationships among the copper (Cu)/zinc (Zn) ratio, inflammatory biomarkers, and the prevalence of diabetic kidney disease (DKD) in patients with type 2 diabetes. MATERIALS AND METHODS: A cross-sectional study was performed on 651 patients with type 2 diabetes. DKD was defined as a urinary albumin-to-creatinine ratio of ≥30 mg/g creatinine and/or an estimated glomerular filtration rate using cystatin C of < 60 mL/min/1.73 m2 . Areas under the curves (AUCs), cutoff values, and thresholds for detecting DKD were determined for the Cu/Zn ratio, soluble tumor necrosis factor-α receptor 1 (sTNFαR1), and high-sensitivity C-reactive protein (hsCRP). Patients were categorized by each cutoff value of sTNFαR1 and the Cu/Zn ratio. Odds ratios (ORs) and biological interactions for the prevalence of DKD were determined. RESULTS: DKD was identified in 220 patients. AUC/optimal cutoff values were 0.777/1300 pg/mL for sTNFαR1, 0.603/1.1648 for the Cu/Zn ratio, and 0.582/305 ng/mL for hsCRP. The ORs for DKD were higher, but not significantly, in the sTNFαR1 < 1300 and Cu/Zn ≥ 1.1648 group, significantly higher in the sTNFαR1 ≥ 1300 and Cu/Zn < 1.1648 group (P < 0.0001), and further synergistically elevated in the sTNFαR1 ≥ 1300 and Cu/Zn ≥ 1.1648 group (P < 0.0001) compared with the sTNFαR1 < 1300 and Cu/Zn < 1.1648 group after multivariable adjustment. Levels of sTNFαR1 were significantly higher in the sTNFαR1 ≥ 1300 and Cu/Zn ≥ 1.1648 group than in the sTNFαR1 ≥ 1300 and Cu/Zn < 1.1648 group (P = 0.0006). CONCLUSIONS: Under an inflammatory initiation signal of elevated serum sTNFαR1 levels, an increase in the Cu/Zn ratio may further exacerbate inflammation and is synergistically associated with a high prevalence of DKD in patients with type 2 diabetes.

Causes of death and estimated life expectancy among people with diabetes: A retrospective cohort study in a diabetes clinic.

We sought to estimate the exact causes of death, mortality rate and life expectancy of diabetes patients by analyzing death records in a diabetes specialist clinic in Japan. Of the 6,140 participants included in our analysis, the average age was 58.1 years and 77% were men. A total of 261 deaths were recorded during the total follow-up period of 24,079 total person-years. The leading causes of death were cancer, heart diseases and cerebrovascular diseases. Using a life table prepared from the mortality rates estimated with the exponential distribution model, a life expectancy at 40 years was 39.2 years (95% confidence interval 37.9-40.2 years) for men and 43.6 years (95% confidence interval 41.8-45.3 years) for women. Although the present results must be interpreted with caution, compared with populations with diabetes surveyed during similar periods by the Japan Diabetes Society, our diabetes patients had similar ranking of the causes of death.

Effect of postprandial hyperglycemia at clinic visits on the incidence of retinopathy in patients with type 2 diabetes: An analysis using real-world long-term follow-up data.

AIMS/INTRODUCTION: There is little evidence on the role of postprandial glycemia in the incidence of diabetic retinopathy (DR) in a real-world setting. We aimed to assess the effect of postprandial hyperglycemia at clinic visits on the incidence of DR in patients with type 2 diabetes, and whether its effect differs depending on glycated hemoglobin (HbA1c) values and age. MATERIALS AND METHODS: Intrapersonal mean blood glucose levels at 1-2 h post-breakfast (1-2h-PBBG), post-lunch (1-2 h-PLBG) and both (1-2h-PBLBG) during 2 years from the first visit were used as baseline data. This retrospective cohort study enrolled 487, 323 and 406 patients who had 1-2h-PBLBG, 1-2h-PBBG and 1-2h-PLBG measurements, respectively. These three groups were followed from 1999 up through 2017. RESULTS: DR occurred in 145, 92 and 126 patients in the 1-2h-PBLBG, 1-2h-PBBG and 1-2h-PLBG groups, respectively. Multivariate Cox regression analysis showed that the mean 1-2h-PBLBG, 1-2h-PBBG and 1-2h-PLBG levels were significant predictors of DR, independent of mean HbA1c. In patients with mean HbA1c <7.0% and those with a baseline age <60 years, the mean 1-2h-PBLBG, 1-2h-PBBG and 1-2h-PLBG levels were significant predictors. CONCLUSIONS: Postprandial hyperglycemia at clinic visits might predict the incidence of DR, independent of HbA1c. The effect of postprandial hyperglycemia on DR is obvious in patients with well-controlled HbA1c and in younger patients. Even with the lower HbA1c level, correcting postprandial hyperglycemia is important for preventing DR, especially in middle-aged adults with type 2 diabetes.

Alpha-Blockers As Colorectal Cancer Chemopreventive: Findings from a Case-Control Study, Human Cell Cultures, and In Vivo Preclinical Testing.

A retrospective case-controlled analysis was performed to identify drug candidates in the current use that may prevent colorectal cancer, outside of aspirin. A total of 37,510 patients aged ≥20 years were assessed to identify subjects who had been diagnosed with colorectal cancer by colonoscopy without a previous diagnosis of colorectal cancer, inflammatory bowel disease (IBD), or gastrointestinal symptoms; 1,560 patients were identified who were diagnosed with colorectal cancer by colonoscopy. The patients with colorectal cancer were matched with 1,560 age, gender, family history of colorectal cancer and comorbidity-matched control patients who were not diagnosed with colorectal cancer at colonoscopy. The medication histories were compared between the two groups. Next, candidate drugs that were more frequently used by the control patients were selected and their effects on human colorectal cancer cell lines in vitro and an inflammation-induced mouse model of colorectal cancer were tested. Putative colorectal cancer preventative agents were identified, including aspirin, vitamin D, vitamin B, vitamin C, vitamin E, xanthine oxidase inhibitor, alpha-blockers, angiotensin receptor blocker, nateglinide, probiotics, thienopyridine, folic acid, nitrovasodilators, bisphosphonates, calcium channel blockers, steroids, and statins (P < 0.05). Alpha-blockers and xanthine oxidase inhibitors were selected for further study because these agents have not been analyzed previously as factors that may affect colorectal cancer outcomes. In vitro doxazosin (alpha-blocker), but not febuxostat (xanthine oxidase inhibitor), suppressed the proliferation of human colorectal cancer cells. Doxazosin also decreased tumorigenesis in an AOM/DSS mouse colorectal cancer model. Alpha-blockers may prevent colorectal cancer.

Optimal cutoff values of fasting plasma glucose (FPG) variability for detecting retinopathy and the threshold of FPG levels for predicting the risk of retinopathy in type 2 diabetes: A longitudinal study over 27 years.

AIMS: To determine the cutoff values of fasting plasma glucose (FPG) variability for detecting retinopathy and examine the threshold of FPG levels for predicting retinopathy incidence in type 2 diabetes. METHODS: Subjects comprised 170 patients with type 2 diabetes who had no retinopathy at their first visit, and continuously visited thereafter for 27 years. Retinopathy was evaluated by ophthalmologists at least annually. RESULTS: 114 patients developed retinopathy. 46 of them had advanced retinopathy. The optimal cutoff values of intrapersonal mean and standard deviation (SD) of FPG over 27 years and intrapersonal mean HbA1c from the initial measurement to the last visit for detecting retinopathy were 7.4 mmol/L, 1.4 mmol/L, and 7.2% (56 mmol/mol), respectively. Similarly, for advanced retinopathy, 7.7 mmol/L, 1.9 mmol/L, and 7.5% (59 mmol/mol), respectively. Hazard ratios of deciles of intrapersonal mean FPG (mmol/L) during the initial 2 years for retinopathy incidence significantly increased from eighth-decile (6.9-7.4), and were sharply elevated from ninth-decile (7.4-8.7). CONCLUSIONS: Our study provides new cutoff values for FPG variability. Cutoff values of FPG and HbA1c were slightly higher than recommended targets of the current guideline. The threshold of FPG levels (6.9 mmol/L) is proposed to predict retinopathy incidence during the subsequent 25 years.

Decline in perception of acid regurgitation symptoms from gastroesophageal reflux disease in diabetes mellitus patients.

OBJECTIVES: To determine if a discrepancy exists between subjective symptoms and the grade of endoscopic gastroesophageal reflux disease (GERD) in diabetes mellitus (DM) patients. METHODS: All 2,884 patients who underwent esophagogastroduodenoscopy completed the modified Gastrointestinal Symptom Rating Scale (GSRS), an interview-based rating scale consisting of 16 items including a question on acid regurgitation. Patients were divided into DM and non-DM groups (1,135 and 1,749 patients, respectively). GERD was diagnosed endoscopically and graded according to the Los Angeles classification. Grade B or more severe GERD was defined as severe endoscopic GERD. The intergroup GSRS score was compared statistically. RESULTS: In severe endoscopic GERD patients, the prevalence of patients with a positive GSRS score in the acid regurgitation question was statistically lower in DM patients than non-DM patients. Of the 60 non-DM patients with severe endoscopic GERD, 40 patients (67%) had a positive GSRS score for acid regurgitation; however, of the 51 DM patients with severe endoscopic GERD, 23 patients (45%) had a positive GSRS score. Multivariate analysis showed that severe endoscopic GERD (OR: 2.01; 95% CI: 1.21-3.33; p = 0.0066), non-DM (OR: 0.74; 95% CI: 0.54-0.94; p = 0.0157), younger age (OR: 0.98; 95% CI: 0.97-0.99; p = 0.0125), and hiatal hernia (OR: 1.46; 95% CI: 1.12-1.90; p = 0.0042) were associated with acid regurgitation symptoms. CONCLUSIONS: There is a discrepancy between subjective symptoms and endoscopic GERD grade in DM patients. The ability of DM patients to feel acid regurgitation may be decreased.

Analysis of the effect of seasonal administration on the efficacy of sitagliptin: Subanalysis of the Januvia Multicenter Prospective Trial in Type 2 Diabetes Study.

AIMS/INTRODUCTION: Hemoglobin A1c (HbA1c) levels in patients with type 2 diabetes mellitus fluctuate throughout the year. However, there are few studies that have evaluated the therapeutic effect of hypoglycemic agents while considering such fluctuations. In a multicenter study (Januvia Multicenter Prospective Trial in Type 2 Diabetes Study), pretreatment patients with type 2 diabetes mellitus were divided into seven groups and given sitagliptin for 1 year. The aim of the present study was to evaluate the differences in the therapeutic effect, and the efficacy of sitagliptin in patients with type 2 diabetes mellitus based on the month the administration of the drug began as a subanalysis of the Januvia Multicenter Prospective Trial in Type 2 Diabetes Study. MATERIALS AND METHODS: Patients with type 2 diabetes mellitus were divided into four groups according to the month of initiation of sitagliptin. Changes in HbA1c in each group were compared at 3 and 12 months after administration of sitagliptin. As a negative correlation has been reported between baseline HbA1c and the degree of change after administration of sitagliptin, an analysis using the residual error from the approximate line was carried out. RESULTS: In the analysis of the degree of change in HbA1c, patients in the group in which administration of sitagliptin was started between August and October had the lowest degree of improvement at 3 months after starting sitagliptin. However, there was no significant intergroup difference in improvement at 12 months after the start of sitagliptin. The same result was also obtained in residual analysis. CONCLUSIONS: The present study suggested that the season of administration of sitagliptin influenced the subsequent hypoglycemic effect even after analysis excluding the influence of HbA1c value at the start of treatment. This study provides possibility, showing that seasonal fluctuations have an effect on the efficacy of antidiabetic drugs.

Erratum to: Efficacy and safety of sitagliptin in elderly patients with type 2 diabetes mellitus and comparison of hypoglycemic action of concomitant medications: a subanalysis of the JAMP study.

[This corrects the article DOI: 10.1007/s13340-017-0330-2.].

Renal Function During an Open-Label Prospective Observational Trial of Sitagliptin in Patients With Diabetes: A Sub-Analysis of the JAMP Study.

BACKGROUND: The aim of the study was to determine the effects of sitagliptin on renal function in a diabetic population including patients with normal renal function. METHODS: We analyzed the association between 12-month, 50 mg/day sitagliptin and renal function in outpatients with type 2 diabetes mellitus and poor blood glucose control in a subset of patients in the larger Januvia Multicenter Prospective Trial in Type 2 Diabetes observational study. Stratified analyses of changes in estimated glomerular filtration rate (eGFR) and urinary albumin-to-creatinine ratio (UACR) were performed. Factors associated with changes in eGFR at 3 months were examined by multivariate regression analysis. RESULTS: Of the 779 patients enrolled, 585 were followed up for 12 months. eGFR decreased significantly from baseline at 3 and 12 months in patients with a baseline eGFR of ≥ 90 mL/min/1.73 m2 and in those with a baseline eGFR of ≥ 60 to < 90 mL/min/1.73 m2. Conversely, eGFR tended to increase at 3 and 12 months in patients with a baseline eGFR of ≥ 45 to < 60 mL/min/1.73 m2 and in those with a baseline eGFR of ≥ 30 to < 45 mL/min/1.73 m2. UACR decreased significantly (-21.6 (-46.8, 7.8)) at 3 months in patients with a baseline UACR of ≥ 30 mg/g Cre. Multivariate regression analysis of factors associated with changes in eGFR at 3 months revealed that higher baseline eGFR and greater decline in UACR were associated with more conspicuous decreases in eGFR. CONCLUSIONS: In this group of diabetic patients receiving sitagliptin, eGFR declined in patients with high baseline eGFR, but not in those with a low baseline eGFR.

Changes in Antidiabetic Drug Prescription and Glycemic Control Trends in Elderly Patients with Type 2 Diabetes Mellitus from 2005-2013: An Analysis of the National Center Diabetes Database (NCDD-03).

Objective To analyze the changes in the pharmacotherapy and glycemic control trends in elderly patients with type 2 diabetes mellitus (T2DM) in Japan. Methods We extracted the data of 7,590 patients (5,396 men and 2,194 women; median year of birth: 1945) with T2DM registered in the National Center Diabetes Database for the years 2005 to 2013, and conducted age-stratified (<65, 65-74, and ≥75 years of age) analyses. Results The hemoglobin A1c (HbA1c) levels declined from 2005 to 2013, and for those who received antihyperglycemic drug prescription, the HbA1c levels were lower in the older age group than in the younger age group. In the ≥75 age group, dipeptidyl peptidase-4 inhibitors (DPP4i) became the most frequently prescribed drug (49.1%) in 2013, and sulfonylureas remained the second-most frequently prescribed drug (37.8%) with decreased prescribed doses. The prescription ratio of oral drugs associated with a risk of hypoglycemia was higher in patients ≥75 years of age than in those <75 years of age (40.5% and 26.4%, respectively in 2013), although it showed a downward trend. The prescription rates of insulin for patients ≥75 years of age increased during the study period. Conclusion The pharmacotherapy trends for elderly patients with T2DM changed dramatically in Japan with the launch of DPP4i in 2009. Glycemic control in a considerable portion of the ≥75 age group in Japan was maintained at the expense of potential hypoglycemia by the frequent, although cautious, use of sulfonylureas, glinides and insulin.

Efficacy and safety of sitagliptin in elderly patients with type 2 diabetes mellitus and comparison of hypoglycemic action of concomitant medications: a subanalysis of the JAMP study.

PURPOSE: To determine the efficacy and safety of sitagliptin when used with some therapeutic drugs to treat elderly patients. METHODS: Sitagliptin (50 mg/day) was added to the pre-existing therapy for type 2 diabetes. Changes in the glycated hemoglobin (HbA1c) level after 3 months of treatment were compared with the baseline, and exploratory analysis was performed. These analyses were conducted as subanalyses of the JAMP study, which was an open-label observational study. RESULTS: For patients who were ≥65 years of age, the change in HbA1c level from baseline ranged from -0.50 to -0.87% at 3 months after starting treatment. There was no significant difference in the change in HbA1c level between the patients treated with different concomitant drugs. No significant difference in HbA1c variations at 3 and 12 months from baseline was noted among the three age groups (≥75, 65-74, and <65 years). Multiple regression analysis was performed, and it revealed that patients with higher HbA1c levels at baseline were likely to show decreased HbA1c levels, while those with higher triglyceride (TG) levels were unlikely to show decreased HbA1c levels. CONCLUSION: Sitagliptin has the potential to both improve glycemic control and prevent hypoglycemia, and can be considered a potent alternative drug.

Factors involved in decreasing the therapeutic effect of sitagliptin: a subanalysis of the JAMP study.

OBJECTIVE: As a subanalysis of the Januvia Multicenter Prospective Trial in Type 2 Diabetes (JAMP study), we examined factors that decreased blood glucose control effect of sitagliptin after 3 months and patients requiring an addition or increase of diabetes treatment. METHODS: We selected patients in whom glycated hemoglobin (HbA1c) levels decreased by month 3 after initiation of sitagliptin treatment and conducted two analyses: (1) in patients who did not change drugs until month 12, we compared changes in HbA1c levels between concomitant drugs and examined factors that decreased blood glucose control effect of sitagliptin; (2) compared changes in HbA1c levels and backgrounds between patients who did and did not require an addition to or increased dose of the antidiabetic agent. RESULTS: Four hundred and ninety-eight patients were chosen. In 369 patients without drug change until month 12, changes in HbA1c levels during months 3-12 were not significantly different among concomitant drugs; factors causing rebound HbA1c were smoking and weight gain. Patient characteristics were compared between those who did and did not require an additional drug or a dose increase (n = 114) (n = 384). Drug changes were associated with longer disease duration, younger age, higher rate of smoking, and higher degree of insulin resistance but not with concomitantly administered drugs. CONCLUSION: Smoking and weight gain were factors that decreased the effect of sitagliptin on reducing blood glucose levels. Differences in concomitant drugs did not affect sitagliptin's effects on glycemic control. A dose increase or the addition of the antidiabetic drug was not associated with concomitant drugs.

Glial fibrillary acidic protein (GFAP) is a novel biomarker for the prediction of autoimmune diabetes.

Glial fibrillary acidic protein (GFAP) is expressed in peri-islet Schwann cells, as well as in glia cells, and has been reported to be an autoantigen candidate for type 1 diabetes mellitus (T1DM). We confirmed that the production of the autoantibodies GFAP and glutamic acid decarboxylase 65 (GAD65) was increased and inversely correlated with the concentration of secreted C peptide in female nonobese diabetic mice (T1DM model). Importantly, the development of T1DM in female nonobese diabetic mice at 30 wk of age was predicted by the positive GFAP autoantibody titer at 17 wk. The production of GFAP and GAD65 autoantibodies was also increased in KK-Ay mice [type 2 diabetes mellitus (T2DM) model]. In patients with diabetes mellitus, GFAP autoantibody levels were increased in patients with either T1DM or T2DM, and were significantly associated with GAD65 autoantibodies but not zinc transporter 8 autoantibodies. Furthermore, we identified a B-cell epitope of GFAP corresponding to the GFAP autoantibody in both mice and patients with diabetes. Thus, these results indicate that autoantibodies against GFAP could serve as a predictive marker for the development of overt autoimmune diabetes.-Pang, Z., Kushiyama, A., Sun, J., Kikuchi, T., Yamazaki, H., Iwamoto, Y., Koriyama, H., Yoshida, S., Shimamura, M., Higuchi, M., Kawano, T., Takami, Y., Rakugi, H., Morishita, R., Nakagumi, H. Glial fibrillary acidic protein (GFAP) is a novel biomarker for the prediction of autoimmune diabetes.

Predictive ability of visit-to-visit variability in HbA1c and systolic blood pressure for the development of microalbuminuria and retinopathy in people with type 2 diabetes.

AIMS: We explored whether visit-to-visit variability in both glycated hemoglobin (HbA1c) and systolic blood pressure (SBP) simultaneously predicted the development of microalbuminuria and retinopathy, and whether the predictive ability of these measurements changed according to mean HbA1c and SBP levels in people with type 2 diabetes. METHODS: A retrospective observational cohort study was conducted on 243 type 2 diabetes patients with normoalbuminuria and 486 without retinopathy at the first visit and within 1year thereafter. The two cohorts were followed up from 1995 until 2012. Multivariate and stratified analyses were performed using Cox proportional hazard models. RESULTS: Microalbuminuria developed in 84 patients and retinopathy in 108. Hazard ratios (HRs) for the development of microalbuminuria associated with the coefficient of variation (CV) and variation independent of mean (VIM) of both HbA1c and SBP significantly increased. In participants with a mean SBP <130mmHg, the HRs for the development of retinopathy associated with CV and VIM of HbA1c were abruptly elevated and significant compared with those with a mean SBP ≥130mmHg. CONCLUSIONS: Visit-to-visit variability in both HbA1c and SBP simultaneously predict the development of microalbuminuria. HbA1c variability may predict the development of retinopathy when the mean SBP is normal (<130mmHg).

A positive family history of hypertension might be associated with an accelerated onset of type 2 diabetes: Results from the National Center Diabetes Database (NCDD-02).

Type 2 diabetes, which is characterized by a combination of decreased insulin secretion and decreased insulin sensitivity, can be delayed or prevented by healthy lifestyle behaviors. Therefore, it is important that the population in general understands their personal risk at an early age to reduce their chances of ever developing the disease. A family history of hypertension is known to be associated with insulin resistance, but the effect of a family history of hypertension on the onset of type 2 diabetes has not well been examined. We performed a retrospective study examining patient age at the time of the diagnosis of type 2 diabetes by analyzing a dataset of 1,299 patients (1,021 men and 278 women) who had been diagnosed as having type 2 diabetes during a health checkup. The mean ± standard deviation of the patient age at the time of the diagnosis of diabetes was 49.1 ± 10.4 years for patients with a family history of hypertension and 51.8 ± 11.4 years for patients without a family history of hypertension (p < 0.001). A multivariate linear regression analysis showed a significant association between a family history of hypertension and a younger age at the time of the diagnosis of type 2 diabetes, independent of a family history of diabetes mellitus and a male sex, suggesting that a positive family history of hypertension might be associated with the accelerated onset of type 2 diabetes.

Long-term treatment study of global standard dose metformin in Japanese patients with type 2 diabetes mellitus.

In 169 Japanese patients with type 2 diabetes mellitus with blood glucose levels that were inadequately controlled with diet and exercise therapy alone, or with diet and exercise therapy plus a sulfonylurea (SU) drug, we evaluated the safety and efficacy of global standard dose metformin given up to a maximum daily dose of 2250 mg for 54 weeks. The changes in HbA1c from baseline to the final evaluation visit were -1.32 ± 0.76% for metformin monotherapy and -1.29 ± 0.81% for metformin plus SU, both significantly lower than baseline. The incidences of adverse events and adverse drug reactions were 91.1% (154/169 patients) and 67.5% (114/169 patients), respectively. The most common adverse events were gastrointestinal symptoms, and most of the gastrointestinal symptoms were considered by investigators to be related to metformin treatment. An increased blood lactic acid level was observed in three subjects (1.8%); however, no clinical symptoms were reported, and there was no increase in mean lactic acid concentration throughout the evaluation period. Symptoms of hypoglycemia were reported in 16 patients, all receiving metformin plus SU, but none received metformin monotherapy. There was a decrease in mean body weight. Global standard dose metformin may be useful for maintaining good blood glucose control over the long term in the treatment of type 2 diabetes mellitus in Japanese patients.

Effect of antihyperglycemic drug monotherapy to prevent the progression of mild hyperglycemia in early type 2 diabetic patients: the Japan Early Diabetes Intervention Study (JEDIS).

To effectively prevent the worsening of hyperglycemia in type 2 diabetes mellitus, it is of interest to see the clinical efficacy of early introduction of pharmacotherapy in addition to lifestyle intervention which is not always easy to continue throughout life. This is a randomized unblinded comparative clinical study on suppressive effects of lifestyle intervention alone and additional monotherapies for mild hyperglycemia at an early stage of treatment-naïve type 2 diabetic patients, whose fasting plasma glucose (FPG) and glycosylated hemoglobin (HbA1c) are less than 140 mg/dl and 7.4%, respectively. The control group (group N = arm N) received conventional lifestyle intervention assisted by routine facilities, while the pharmacological intervention group (group D composed of 4 arms) was additionally treated by monotherapy with one of four kinds of oral antihyperglycemic agents i.e., sulfonylurea (SU), α-glucosidase inhibitor, biguanide and dipeptidyl peptidase-4 inhibitor. The participants were scheduled to follow up for 3 years to maintain glycemic control below primary endpoint which was defined as the first occurrence of FPG ≥140 mg/dl and HbA1c ≥7.4% simultaneously even by increasing doses of oral drug in group D, if necessary. The outcomes of occurrences of primary endpoint were not different between group N and group D composed of 4 arms during 3 years by Kaplan-Meyer plots (p = 0.405). On the other hand, ΔFPG (Δ: incremental change from baseline) and ΔHbA1c in group D significantly decreased when compared to those of group N during 3 years (p < 0.05 and p < 0.01 respectively). Significant reductions of ΔBMI were seen similarly in both groups throughout the study (p < 0.05), but did not differ between two groups. Among these 5 arms, significant decreases of ΔHbA1c were observed in three monotherapy arms of group D compared to arm N for 3 years (p < 0.05 or p < 0.01), except for arm SU in which ΔBMI and ΔHbA1c tended to increase at the latter half of the study. The final achievement rates of target HbA1c less than 7.4, 7.0 and 6.5% in all the participants tended to be higher in group D than in group N (p < 0.047 for 7.4%, but not significant for others). In conclusion, the early introduction of pharmacological monotherapy in addition to lifestyle intervention seem to suppress mild hyperglycemia with small doses of antihyperglycemic agents for 3 years, except for the use of SU drug. Although a larger scale of trial will be necessary to conclude, the early treatment with suitable monotherapy could be effective to bring and keep "safe level of glycemia".

Impact of postprandial hyperglycemia at clinic visits on the incidence of cardiovascular events and all-cause mortality in patients with type 2 diabetes.

AIMS/INTRODUCTION: We evaluated the impact of postprandial hyperglycemia at clinic visits on the incidence of cardiovascular diseases (CVD) and all-cause mortality independently of mean glycosylated hemoglobin in type 2 diabetes patients in a real-world setting. MATERIALS AND METHODS: The present retrospective observational cohort study included 646 type 2 diabetes patients. All of the participants had their initial consultations at the Institute for Diabetes Care and Research, Asahi Life Foundation affiliated Marunouchi Hospital, Tokyo, Japan, during the period from 1995 to 1996, visited the clinic ≥4 times, had their 2-h post-breakfast blood glucose (2h-PBBG) levels measured and were followed up for ≥1 year. The 646 patients were followed up for survival. Of the 646 patients, 618 had no history of CVD at the first visit and had measured 2h-PBBG until the first CVD onset or censorings. These two cohorts were followed up through June 2012, and subsequently questionnaires were mailed. Multivariate Cox proportional hazard models were used to evaluate the risk of CVD incidence and death. RESULTS: CVD occurred in 78 patients, and 56 patients died. The median follow-up periods of the CVD cohort and the mortality cohort were 15.6 and 15.9 years, respectively. The mean 2h-PBBG is a significant predictor of the CVD incidence and all-cause mortality after adjusting for the mean glycosylated hemoglobin, the number of 2h-PBBG measurements, age, sex and classical risk factors. CONCLUSIONS: Postprandial hyperglycemia represented by the mean level of 2h-PBBG at clinic visits is associated with CVD incidence and all-cause mortality independently of the mean glycosylated hemoglobin level in type 2 diabetes patients. Prospective interventional trials are warranted to confirm the present findings.

Insulin degludec/insulin aspart vs biphasic insulin aspart 30 twice daily in Japanese patients with type 2 diabetes: A randomized controlled trial.

AIMS/INTRODUCTION: Insulin degludec/insulin aspart (IDegAsp) is a soluble combination of insulin degludec (70%) and insulin aspart (30%). The present exploratory trial investigated the safety of switching unit-to-unit from twice-daily basal or pre-mix insulin to twice-daily IDegAsp in Japanese patients with type 2 diabetes. MATERIALS AND METHODS: In this 6-week, open-label, parallel-group, controlled trial, 66 participants were randomized (1:1) to receive either IDegAsp or biphasic insulin aspart 30 (BIAsp 30) twice daily at the same total daily dose as pre-trial insulin. During the trial, insulin doses were adjusted according to a pre-specified algorithm to achieve pre-breakfast and pre-dinner plasma glucose of 4.4-7.2 mmol/L. RESULTS: No severe hypoglycemic episodes occurred. There were no statistically significant differences in rates of confirmed hypoglycemia (rate ratio IDegAsp/BIAsp 30: 0.63, 95% confidence interval: 0.31-1.30) and confirmed nocturnal hypoglycemia (rate ratio: 0.49, 95% confidence interval: 0.10-2.38) for IDegAsp vs BIAsp 30. The hypoglycemia rate for IDegAsp was constant over the 6 weeks of treatment. IDegAsp and BIAsp 30 were both safe and well tolerated. Reduction in fasting plasma glucose was statistically significantly greater for IDegAsp than for BIAsp 30 (estimated treatment difference, IDegAsp-BIAsp 30: -1.6 mmol/L, 95% confidence interval: -2.4 to -0.8). The apparent decrease in mean postprandial plasma glucose increment (IDegAsp: 4.2-3.8 mmol/L; BIAsp 30: 4.5-2.8 mmol/L) was not statistically significantly different between treatments (estimated treatment difference: 1.0 mmol/L, 95% confidence interval: -0.1 to 2.2). CONCLUSIONS: Switching unit-to-unit from basal or pre-mix insulin to IDegAsp seems not to be associated with any concerns related to hypoglycemia or general safety in Japanese patients with type 2 diabetes.

Effect of sitagliptin on blood glucose control in patients with type 2 diabetes mellitus who are treatment naive or poorly responsive to existing antidiabetic drugs: the JAMP study.

BACKGROUND: To investigate the ameliorating effect of sitagliptin, a dipeptidyl peptidase-4 inhibitor, on blood glucose control in patients with type 2 diabetes mellitus who were previously untreated with or who have a poor responsive to existing antidiabetic drugs. METHODS: Sitagliptin (50 mg/day) was added on to the pre-existing therapy for type 2 diabetes and changes in the glycated hemoglobin (HbA1c) level after 3 months of treatment were compared with the baseline and performed exploratory analysis. RESULTS: HbA1c levels were significantly decreased after 1 month of treatment compared to baseline, with a mean change in HbA1c level from baseline of -0.73% (range, -0.80 to -0.67) in the entire study population at 3 months. Patients who received a medium dose of glimepiride showed the least improvement in HbA1c levels. The percentage of patients who achieved an HbA1c level of <7.0% significantly increased after 1 month of treatment, reaching 53.1% at 3 months. The percentage of patients who achieved a fasting blood glucose level of <130 mg/dL significantly increased after 1 month of treatment, reaching 50.9% at 3 months. CONCLUSIONS: Sitagliptin improved the HbA1c level and rate of achieving the target control levels in patients with type 2 diabetes mellitus who were previously untreated with, or poorly responsive to, existing antidiabetic drugs. Thus, sitagliptin is expected to be useful in this patient group. However, the additional administration of sitagliptin in patients treated with medium-dose glimepiride only slightly improved blood glucose control when corrected for baseline HbA1c level.